John Svaren, PhD
Position title: Professor, Comparative Biosciences

PhD, Vanderbilt University
Director, IDD Models Core
Contact Information
Waisman Center
Room 659
1500 Highland Avenue
Madison, WI 53705
608.263.4246
jpsvaren@wisc.edu
Lab Website: Svaren Lab Home Page
School of Veterinary Medicine
Research Statement
The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons. Some peripheral neuropathiesincluding Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN)are caused by deficits in myelin formation and maintenance by Schwann cells. Most of the genetic causes of these peripheral neuropathies have been traced to mutations in genes coding for myelin-associated proteins (e.g. myelin protein zero). However, mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases, confirming previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The identification of a critical transcriptional activator in the myelination process has allowed us an opportunity to understand how coordinated regulation of many genes contributes to the myelination process.
Our research goal is to elucidate the mechanisms of transcriptional control that become altered in peripheral nerve diseases associated with EGR2 mutations. Several neuropathy-associated mutations inhibit DNA-binding by EGR2, but all of these mutations are dominant. This finding is surprising since only one functional allele of EGR2/Krox-20 is sufficient for myelin formation in mice. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions have suggested that interaction with another regulator, Sox10, is critically involved. Finally, one of the EGR2 mutations alters a domain that interacts with the NAB family of corepressor/coactivator proteins. This recessive mutation therefore strongly implicates the NAB proteins as important regulators of myelination. Therefore, we are also focusing on the use of both gene microarrays and quantitative PCR assays to try to understand how EGR2 and NAB proteins regulate a gene network that controls myelination of peripheral nerves by Schwann cells.
The spectrum of peripheral myelinopathies (including CMT, DSS, and CHN) cause a variety of clinical problems and the more severe cases often result in premature death due to decreased respiratory function. However, there is great promise for therapies that treat this type of disease since the affected Schwann cells remain viable during the course of the disease. Even in more severe cases, the normal time of myelin formation (during the first year of life) should allow restorative therapy in those cases where a specific genetic cause is identified. Other types of therapy based on rapidly developing stem cell technologies are also strong possibilities. Because EGR2 coordinates gene regulation events that are vital for proper myelination of peripheral nerves, development of any of these therapies will clearly benefit from elucidation of the genetic program controlled by EGR2 and NAB proteins.
Selected Publications
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Park, H. J., Tsai, E., Huang, D., Weaver, M., Frick, L., Alcantara, A., Moran, J. J., Patzig, J., Melendez-Vasquez, C. V., Crabtree, G. R., Feltri, M. L., Svaren, J., & Casaccia, P. (2022). ACTL6a coordinates axonal caliber recognition and myelination in the peripheral nerve. iScience, 25(4), 104132. https://doi.org/10.1016/j.isci.2022.104132
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Wang, H., Davison, M., Wang, K., Xia, T. H., Call, K. M., Luo, J., Wu, X., Zuccarino, R., Bacha, A., Bai, Y., Gutmann, L., Feely, S., Grider, T., Rossor, A. M., Reilly, M. M., Shy, M. E., & Svaren, J. (2021). MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A. Neurology, 97(5), e489–e500. https://doi.org/10.1212/WNL.0000000000012266
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Duong, P., Ma, K. H., Ramesh, R., Moran, J. J., Won, S., & Svaren, J. (2021). H3K27 demethylases are dispensable for activation of Polycomb-regulated injury response genes in peripheral nerve. The Journal of biological chemistry, 297(1), 100852. https://doi.org/10.1016/j.jbc.2021.100852
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Grosz, B. R., Svaren, J., Perez-Siles, G., Nicholson, G. A., & Kennerson, M. L. (2021). Revisiting the pathogenic mechanism of the GJB1 5′ UTR c.-103C > T mutation causing CMTX1. Neurogenetics, 22(3), 149–160. https://doi.org/10.1007/s10048-021-00650-9
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Martinez, N. J., Braisted, J. C., Dranchak, P. K., Moran, J. J., Larson, H., Queme, B., Pak, E., Dutra, A., Rai, G., Cheng, K. C., Svaren, J., & Inglese, J. (2021). Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for PMP22 Gene-Dosage Disorder Drug Discovery. ACS pharmacology & translational science, 4(4), 1422–1436. https://doi.org/10.1021/acsptsci.1c00110
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Lupo, V., Won, S., Frasquet, M., Schnitzler, M. S., Komath, S. S., Pascual-Pascual, S. I., Espinós, C., Svaren, J., & Sevilla, T. (2020). Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex. European journal of neurology, 27(12), 2662–2667. https://doi.org/10.1111/ene.14512
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Pantera, H., Hu, B., Moiseev, D., Dunham, C., Rashid, J., Moran, J. J., Krentz, K., Rubinstein, C. D., Won, S., Li, J., & Svaren, J. (2020). Pmp22 super-enhancer deletion causes tomacula formation and conduction block in peripheral nerves. Human molecular genetics, 29(10), 1689–1699. https://doi.org/10.1093/hmg/ddaa082
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Wang H, Davison M, Wang K, Xia TH, Kramer M, Call K, Luo J, Wu X, Zuccarino R, Bacon C, Bai Y, Moran JJ, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Svaren J, Shy ME. (2020). Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A. Annals of Clinical and Translational Neurology, 7(1):69-82. doi: 10.1002/acn3.50965.
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Pantera H, Shy ME, Svaren J. (2020). Regulating PMP22 expression as a dosage sensitive neuropathy gene. Brain Research, 1;1726:146491. doi: 10.1016/j.brainres.2019.146491.
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Svaren J, Moran JJ, Wu X, Zuccarino R, Bacon C, Bai Y, Ramesh R, Gutmann L, Anderson DM, Pavelec D, Shy ME. (2019). Schwann Cell Transcript Biomarkers for Hereditary Neuropathy Skin Biopsies. Annals of Neurology, 85(6):887-898. doi: 10.1002/ana.25480.
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Belin S, Ornaghi F, Shackleford G, Wang J, Scapin C, Lopez-Anido C, Silvestri N, Robertson N, Williamson C, Ishii A, Taveggia C, Svaren J, Bansal R, Schwab MH, Nave K, Fratta P, D’Antonio M, Poitelon Y, Feltri ML, Wrabetz L. (2019). Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy. Human Molecular Genetics, 28(8):1260-1273. doi: 10.1093/hmg/ddy420.
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Tao F, Beecham GW, Rebelo AP, Blanton SH, Moran JJ, Lopez-Anido C, Svaren J, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. (2019). Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study. Journal of Neuromuscular Diseases, 6(2):201-211. doi: 10.3233/JND-190377.
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Tao F, Beecham GW, Rebelo AP, Blanton SH, Moran JJ, Lopez-Anido C, Svaren J, Morrow JM, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. (2019). Variation in SIPA1L2 is Correlated with Phenotype Modification in CMT Type 1A. Annals of Neurology, 85(3):316-330. doi: 10.1002/ana.25426
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Ma KH, Svaren J. (2018). Epigenetic Control of Schwann Cells. Neuroscientist, 24(6):627-638. doi: 10.1177/1073858417751112.
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Zhao HT, Damle S, Ikeda-Lee K, Kuntz S, Li J, Mohan A, Kim A, Hung G, Scheideler MA, Scherer SS, Svaren J, Swayze EE, Kordasiewicz HB. (2018). PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models. Journal of Clinical Investigation. 128(1):359-368. doi: 10.1172/JCI96499.
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Duncan ID, Bugiani M, Radcliff AB, Moran JJ, Lopez-Anido C, Duong P, August BK, Wolf NI, van der Knaap MS, Svaren J. (2017) A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. Annals of Neurology. 81(5):690-702. doi: 10.1002/ana.24930.
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Rodríguez-Molina JF, Lopez-Anido C, Ma KH, Zhang C, Olson T, Muth KN, Weider M, Svaren J. (2017) Dual specificity phosphatase 15 regulates Erk activation in Schwann cells. Journal of Neurochemistry. 140(3):368-382. doi: 10.1111/jnc.13911.
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Gopinath C, Law WD, Rodríguez-Molina JF, Prasad AB, Song L, Crawford GE, Mullikin JC, Svaren J, Antonellis A. (2016) Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation. BMC Genomics. 17(1):887.
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Ma KH, Hung HA, Svaren J. (2016) Epigenomic Regulation of Schwann Cell Reprogramming in Peripheral Nerve Injury. Journal of Neuroscience. 36(35):9135-47. doi: 10.1523/JNEUROSCI.1370-16.2016.
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Fogarty EA, Brewer MH, Rodriguez-Molina JF, Law WD, Ma KH, Steinberg NM, Svaren J, Antonellis A. (2016) SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. Human Molecular Genetics. 15;25(18):3925-3936. doi: 10.1093/hmg/ddw233.
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Poitelon Y, Lopez-Anido C, Catignas K, Berti C, Palmisano M, Williamson C, Ameroso D, Abiko K, Hwang Y, Gregorieff A, Wrana JL, Asmani M, Zhao R, Sim FJ, Wrabetz L, Svaren J, Feltri ML. (2016) YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells. Nature Neuroscience. 19(7):879-87. doi: 10.1038/nn.4316.
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Lopez-Anido C, Poitelon Y, Gopinath C, Moran JJ, Ma KH, Law WD, Antonellis A, Feltri ML, Svaren J. (2016) Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development. Human Molecular Genetics. 15;25(14):3055-3069.
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Lopez-Anido C, Sun G, Koenning M, Srinivasan R, Hung HA, Emery B, Keles S, Svaren J. (2015) Differential Sox10 genomic occupancy in myelinating glia. Glia, 63:1897–1914. doi: 10.1002/glia.22855.
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Romens SE, McDonald J, Svaren J, Pollak SD. (2015) Associations Between Early Life Stress and Gene Methylation in Children. Child Development. 86(1):303-9. doi: 10.1111/cdev.12270.
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Ma KH, Hung HA, Srinivasan R, Xie H, Orkin SH, Svaren J. (2015) Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2. Journal of Neuroscience, 35(22):8640-52. doi: 10.1523/JNEUROSCI.2257-14.2015.
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Hung HA, Sun G, Keles S, Svaren J. (2015) Dynamic regulation of Schwann cell enhancers after peripheral nerve injury. Journal of Biological Chemistry, 13;290(11):6937-50. doi: 10.1074/jbc.M114.622878.
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Inglese J, Dranchak P, Moran JJ, Jang SW, Srinivasan R, Santiago Y, Zhang L, Guha R, Martinez N, MacArthur R, Cost GJ, Svaren J. (2014) Genome Editing-Enabled HTS Assays Expand Drug Target Pathways for Charcot-Marie-Tooth Disease. ACS Chemical Biology. 21;9(11):2594-602. doi: 10.1021/cb5005492.
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Sun G, Srinivasan R, Lopez-Anido C, Hung HA, Svaren J, Keleş S. (2014) In Silico Pooling of ChIP-seq Control Experiments. PLoS One. 9(11):e109691.
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Brewer MH, Ma KH, Beecham GW, Gopinath C, Baas F, Choi BO, Reilly MM, Shy ME, Züchner S, Svaren J, Antonellis A. (2014) Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2. Human Molecular Genetics. 23(19):5171-87.
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Svaren J. (2014) MicroRNA and transcriptional crosstalk in myelinating glia. Neurochemistry International. 77:50-7.
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Jones EA, Brewer MH, Srinivasan R, Krueger C, Sun G, Charney KN, Keles S, Antonellis A, Svaren J. (2012) Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22. Human Molecular Genetics. Apr 1;21(7):1581-91.
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Oliver SS, Musselman CA, Srinivasan R, Svaren JP, Kutateladze TG, Denu JM. (2012) Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry. 51(33):6534-44.
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Hodonsky CJ, Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA, Srinivasan R, Svaren J, McCallion AS, Antonellis A. (2012) SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Molecular and Cellular Biology. Feb;49(2):85-96.
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Gokey NG, Srinivasan R, Lopez-Anido C, Krueger C, Svaren J. (2012) Developmental regulation of microRNA expression in Schwann cells. Molecular and Cellular Biology. Jan;32(2):558-68.
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Srinivasan R, Sun G, Keles S, Jones EA, Jang SW, Krueger C, Moran JJ, Svaren J. (2012) Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve. Nucleic Acids Research. 40(14):6449-60.
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Hung H, Kohnken R, Svaren J. (2012) The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. Journal of Neuroscience. Feb 1;32(5):1517-27.
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Gokey NG, Lopez-Anido C, Gillian-Daniel AL, Svaren J. (2011) Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression. Journal of Biological Chemistry. Aug 26;286(34):29501-10.